The title compound was discovered as a useful synthetic adrenergic drug with many applications because of its vasoconstricting activity. For a number of years ‘phenylephrine’ was used as its racemic mixture including some of its prodrugs (see: Legerlotz, U.S. Pat. No. 1,932,347; Hussain et al, U.S. Pat. No. 3,825,583; Bodor et al, U.S. Pat. No. 4,028,368 and U.S. Pat. No. 4,158,005). Although recognized as the more active form the levorotatory isomer (R)-phenylephrine was marketed only much later. It was also assumed that the racemic phenylephrine undergoes racemization in presence of acids in the gastric chamber like some of the catecholamines and pseudoephedrine. However, Legerlotz (see: DE 585164 C) had reported that high pressure heating with hydrochloric acid for a number of hours was required to inactivate ‘active’ phenylephrine, leading mostly to a small fraction of the substance to its racemic mixture and to other unidentified substances. In a series of articles in J. Pharmacol. Exptl. Therap., from 1967 to 1972 with the general title “Steric aspects of adrenergic drugs”, Patil et al have demonstrated the superiority of dextro-isomers over the levo-isomers of several sympathomimetic phenylethyl amines, including l-phenylephrine or (R)-phenylephrine (Formula 2). Several methods of synthesizing the molecule of Formula 1 below have been reported in literature leading to the formation of the racemic mixture. There is no published method of resolution of the racemic mixture of the molecule into its l-isomer and its isolation. Legerlotz has described (DE 543529) a method of resolving 1-(2-hydroxyphenyl)-2-methylamino ethanol and 1-(4-hydroxyphenyl)-2-methylamino ethanol with resolving agents like (+)-tartaric acid, d-camphorsulfonic acid and l-bromocamphorsulfonic acid. However, the undesired d-isomers of the amino alcohols only crystallized, the required isomers remaining in the mother liquors. A tedious work up is needed to recover the desired amino alcohol from the mother liquor. The yields of the isomers are not given. The specific rotation of the recovered undesired isomer is recorded but not that of the desired l-isomers. No procedure is given for the recovery of the desired isomer from the mother liquor. More to the point, it is to be noted that no example for the corresponding 3-hydroxyphenyl analog, the subject of this application, is described.

However, there are several asymmetric methods of synthesis reported for obtaining the R-isomer. These make use of the prochiral ketone precursor (Formula 3) for asymmetric reduction (hydrogenation) with catalysts containing transition metals like ruthenium, rhodium and iridium more frequently, along with complex chiral ligands. (see: IN 221620, U.S. Pat. No. 6,187,956, WO 2008 077560, WO 2009 086283, Takeda et al, Tetrahedron Letters, 1989, 30 367-370). In most of these processes the phenolic group or the secondary amino group or both, are protected and later deprotected. Recently reduction of α-haloketone (Formula 4) without protection of the phenolic group has been achieved using a microbial alcohol dehydrogenase enzyme from Aromatoleum aromaticum or Azoarcus sp. (See: WO 2010 031776). In this process the methylamino group is introduced last, i.e. after resolution.
Gurjar et. al. have described another approach by kinetic resolution of a racemic styrene oxide (Formula 5) in presence of a complex ligand followed by isolation of the required isomer and reaction with methylamine to give (R)-phenylephrine, (Org. Proc. Res. Dev., 1998, 2, 422-424). The starting material is 3-hydroxy benzaldehyde which is more expensive than the usual 3-hydroxy acetophenone. Besides there is necessity of protecting the phenolic group and deprotecting it at later stage and use of an expensive complex chiral ligand. All these methods suffer from expensive chiral ligands and metallic catalysts, high pressure hydrogenations, etc. Thus there is a need for an efficient method of separation of the optical isomers of phenylephrine and a viable recovery of the required (R)-phenylephrine.
